The invention relates to a method and a device for monitoring the concentration of a selected substance or group of substances in a body fluid of a living human or animal body.
A method for the above-mentioned purpose in which the substance or group of substances to be monitored is transferred from the body through an interface and away from behind the interface in a perfusion fluid flow, and in which the concentration of the substance or group of substances to be monitored in the perfusion fluid flow is measured downstream from the interface is known from International Patent Application publ. no. WO 89/02720.
The specific purpose of this known method is monitoring the glucose concentration in blood. The interface used is a subcutaneously inserted microdialysis membrane through which glucose diffuses from the blood into the perfusion fluid which is circulated at a flow rate of 100 to 1000 .mu.l/hour and preferably between 200 and 400 .mu.l/hour. Glucose which has entered the perfusion fluid is oxidized by oxygen in the perfusion fluid in the presence of a glucoseoxidase enzyme. The amount of H.sub.2 O.sub.2 formed or the amount of O.sub.2 consumed is determined, each of which are a measure of the glucose concentration in the perfusate and therefore an indication of the glucose concentration of the blood.
Information on the concentration of the selected substance or group of substances is obtained without having to take fluid samples each time information is desired. Moreover, the information can be provided continuously, so the concentration can be monitored with a minimal, constant delay.
The monitoring results can for example be used for watching over a patient and as input data for determining or correcting the dose of one or more substances to be administered to that patient, such as insulin and glucose (artificial pancreas).
The interface and the detector used in this known method are part of a wearable device, which furthermore comprises an enzyme metering system and a perfusion pump for driving the perfusate along the interface and the detector. Furthermore, the device will also need energy for the perfusion pump, which may for example be provided by a battery.
A problem of such devices is to provide a pump which provides a continuous constant flow, which is compact, not excessively expensive and of a simple reliable construction. Known pumps, although reasonably accurate over a longer period of time, typically generate a pulsatile or somewhat fluctuating flow. When a device with such a pump is used for monitoring, a pulsating or fluctuating measurement result is obtained. One tentative solution would be to cancel these variations out by calculating a running average over a sufficiently large window of time, but this would increase the measurement delay and reduce the time resolution and the sensitivity to peak values.
Furthermore, the weight and the dimensions of this known device have a negative impact on wearing comfort, cause the device to interfere with a patient's clothing and daily activities and increase the risk of damage to and dislocation of the device. A particular group of patients for whom size and weight of the device is very critical are neonates under intensive care in incubators. Such patients often weigh less than 2 kg. Another disadvantage of relatively substantial dimensions is that they limit the positions on the body where the device can be worn to some limited parts of the body which will not always be on or near preferred locations for the interface, such as on the forearm or the belly. If use is made of an invasively positioned interface, preferably widely varying locations should be available to avoid repeated damage to a limited area of a patient's body.
Because the device has a complicated structure, it is costly and relatively unreliable. Reliability is of particular importance if the monitored concentrations are used as input data for administering a substance such as a medicament.
In "An Enzyme-Selector for Electrochemical Monitoring of Choline and Acetylcholine: Applications in High Performance Fluid Chromatography, Brain Tissue, Microdialysis and Cerebrospinal Fluid" by Flentge et al. in Analytical Biochemistry 204, pages 305-310 (1992), an experiment is described in which enzymes are used for monitoring choline of a rat by brain dialysis. The device used in this small animal experiment also comprises a microdialysis interface which is placed intracerebrally. The flow rate of the perfusate is described to be 1 .mu.l/min.
The device used in this experiment does not comprise means for metering enzymes, but the enzymes are physically immobilized between two membranes in a selector upstream from the detector. A pump for driving the perfusion fluid flow is also included in this device. This device is described as a laboratory set-up. A functionally identical dedicated device would be very large and would have a complicated structure.
In European patent application 0 134 758 a device is described in which a solution is pumped from a reservoir, through an implantable semi-permeable hollow-fibre circuit and to a sensor and then to a waste reservoir or back to the first-mentioned reservoir by means of a pump. To obtain an equilibrium between the concentrations of the substance to be monitored in the tissue and in the hollow-fibre circuit, the implantable hollow-fibre circuit has a great length. To enable implantation of the long hollow-fibre circuit, it is formed in a spiral shape sustained by a disk.
Since the hollow-fibre circuit has a substantial size, it has to be implanted surgically by making an incision in the skin and it has to be displaced at least every two weeks, which requires new surgery. Moreover, this device also comprises a pump and a battery which has to be relatively large to supply sufficient energy for pumping the solution through the hollow-fibre circuit. Both these items substantially contribute to the size and the weight of the device.